Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opiates modulate pain perception at a number of different levels within the central nervous system and the importance of synergistic spinal and supraspinal influences have been well documented. In the present study we demonstrate synergistic interactions between the periaqueductal gray and locus coeruleus. Administered either systemically or intracerebroventricularly (i.c.v.), ethylketocyclazocine elicits a potent naloxonazine-sensitive analgesia, indicating a mu 1 action. mu 1 Receptors also play a major role in opioid analgesic mechanisms in the periaqueductal gray and the locus coeruleus. However, microinjection of EKC into either the periaqueductal gray or locus coeruleus failed to elicit an analgesic response at any dose tested (0.1-20 micrograms) and, in additional studies, antagonized the analgesic actions of coadministered morphine or [D-Ser2,Leu5]enkephalin-Thr6 (DSLET). However, the simultaneous administration of EKC into both the periaqueductal gray (10 micrograms) and the locus coeruleus (10 micrograms; total combined dose 20 micrograms) produced a potent naloxonazine-sensitive analgesia greater than that observed with 50 micrograms i.c.v. These results suggest that EKC is a partial mu 1 agonist which lacks the efficacy to elicit analgesia when microinjected into either of the two brain regions alone. However, when exposed to several regions at once, either through simultaneous microinjections into the periaqueductal gray and locus coeruleus or by injection into the ventricle, EKC is a potent mu 1 analgesic. These results point out the existence of synergistic supraspinal interactions between the periaqueductal gray and the locus coeruleus, similar to the spinal/supraspinal interactions observed previously.
 ...
PMID:Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus. 166 70

The pharmacological effects of morphine, namely analgesic, hyperthermic and cataleptic effects, were assessed in rats rendered tolerant to U-50,488H, a kappa opioid receptor agonist. Male Sprague-Dawley rats were injected intraperitoneally with U-50,488H (25 mg/kg) twice a day for four days. The rats which served as controls were injected similarly with the vehicle. Chronic administration of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic effects, but not to its diuretic effect. The development of tolerance to the pharmacological effects of U-50,488H was associated with decreased binding of [3H]ethylketocyclazocine [( 3H]EKC) to brain and spinal cord membranes. The decreased binding of [3H]EKC in U-50,488H-treated rats was due to changes in the Bmax value; the Kd values remained unaltered. Intraperitoneal administration of morphine (8 mg/kg) to rats produced analgesia (as determined by the tail-flick test) and hyperthermia. A dose of 50 mg/kg of morphine produced cataleptic response. The intensity of analgesic, hyperthermic and cataleptic effects of morphine were unaltered in rats tolerant to U-50,488H. The development of tolerance to analgesic and hypothermic effects of U-50,488H were associated with down-regulation of brain and spinal cord kappa opioid receptors. Finally, U-50,488H does not confer cross-tolerance to morphine, a predominantly mu opioid receptor agonist.
 ...
PMID:Effects of morphine in rats treated chronically with U-50,488 H, a kappa opioid receptor agonist. 254 58

Opiates and opioid peptides were administered in the order of 10(-9)-10(-6) mol peripherally, and their action on pain sensitivity was investigated by the modified formalin test which has two characteristic pain responses (the first and the second phase) in the mouse hindpaw. Opioid peptides (20-500 pmol) had dose-dependent analgesia against both first and second phases, and their action ranked dynorphin greater than [D-Ala2, Met5]-enkephalinamide greater than [Met5]-enkephalin. EKC and morphine (0.4-2.5 nmol) inhibited pain response of the first phase, but produced hyperalgesia in the second phase dose-dependently. Lidocaine hydrochloride had peripheral analgesic action, but was about 500-10000 times weaker than these substances. So, these peripheral analgesic actions have a different mechanism from that of local anesthetic action. N-methyl levallorphan which is thought to be a peripherally selective narcotic antagonist reversed these peripheral analgesic actions at the first and second phases and also prevented the hyperalgesic effects of EKC and morphine at the second phase. Naloxone reversed analgesia at only the first phase. These results suggest that an analgesic mechanism by opioids may exist at the peripheral site as well. Furthermore, it is estimated that a receptor exists which is antagonized by N-methyl levallorphan but not by naloxone and that there is a system of hyperalgesia by EKC and morphine in pain modulation.
 ...
PMID:[Peripheral analgesic actions of opioid peptides and morphine analogues]. 287 30

In vivo pharmacological data support the concept of mu (mu) isoreceptors in the rat CNS. The mu 1 receptor mediates analgesia and regulation of cholinergic neurons. Naloxazone may be a specific antagonist of this receptor type. In contrast, the mu 2 receptor is responsible for respiratory depression and regulation of nigrostriatal dopaminergic neurons. In this case, the kappa agonists EKC and MR-2034 appear to be specific mu 2 antagonists.
 ...
PMID:Mu opiate isoreceptors: differentiation with kappa agonists. 613 59

U-50,488H is a chemically novel analgesic that is a potent opioid-like agent on the mouse tail flick and electrically stimulated guinea pig ileum tests. U-50,488H is a very weak competitor for naloxone binding sites in brain and ileum. However, the drug has high affinity for kappa receptor binding sites revealed by competition for EKC sites in the presence of dihydromorphine. Morphine has both supraspinal and spinal sites of action since it was a potent analgesic after both intracranial and intraspinal injections. However, U-50,488H works predominantly at the spinal level. Dynorphin may be an endogenous ligand at this site. Studies on cat dorsal horn neurons suggest that U-50,488H analgesia may be due to an increase in threshold for neuron excitation.
 ...
PMID:U-50488H, a pure kappa receptor agonist with spinal analgesic loci in the mouse. 629 8

Local anaesthetics and opioid drugs function synergistically to provide analgesia. In the present study, the nature of this synergy has been investigated using in vitro radioligand binding to determine whether the local anaesthetics bupivacaine and tetracaine modulate the binding of two kappa-opioid receptor ligands, [3H]U-69593 (5-alpha,7-alpha,8-beta-(-)-N-methyl-N[7-(1-pyrrolodinyl)-1-oxa spiro(4,5)dec-8-yl]-benzene acetamide) and [3H](-)-EKC (ethylketocyclazocine). [3H]U-69593 bound with a KD of 0.88 nM and a Bmax of 2.39 +/- 0.22 fmol/mg wet weight in guinea pig cerebellar membranes. The binding was inhibited by bremazocine and morphine with Hill slopes near unity and pI50 values of 9.96 and 6.84-6.86, respectively. [3H]U-69593 binding was inhibited by Gpp(NH)p (5'-guanylyl imidodiphosphate) and NaCl, consistent with an agonist action of the compound. The binding characteristics of the ligand were not changed by bupivacaine or tetracaine. [3H](-)-EKC bound with KD values of 0.55 and 0.97 nM and Bmax values of 4.22 and 0.99 fmol/mg wet weight in guinea pig cerebellar membranes and rat spinal cords, respectively. In the rat spinal cord, [3H](-)-EKC appeared to act as an agonist/antagonist, since the presence of Gpp(NH)p and NaCl only produced a small (21%) reduction in binding, but reduced the pI50 for the residual binding to inhibition by morphine from 6.33-6.39 to 5.95. As with [3H]U-69593, the binding characteristics of [3H](-)-EKC were not affected by bupivacaine or tetracaine. These studies demonstrate that effects of kappa-opioid receptor recognition site conformation are unlikely to explain the clinically observed synergy between local anaesthetics and opioids.
 ...
PMID:kappa-Opioid receptor recognition sites are not modulated by local anaesthetics. 774 60

The effects of ethylketazocine, U-50,488, morphine and (-)-nicotine administered both i.p. and into the mid-fourth ventricle of intact rats were investigated using a conventional high intensity tail-flick reflex and one evoked with a lower intensity thermal stimulus. The sensitivity of the low intensity thermally evoked tail avoidance reflex was several times that of a high intensity tail-flick reflex in detecting the analgesic activity of morphine and yielded valid assays and relative potencies between morphine (1), EKC (18.76) and U-50,488 (0.23) when the drugs were administered ip. When the opioid drugs were administered into the fourth ventricle they produced a dose-related shortening of the latency of the low intensity thermally evoked tail avoidance reflex. (-)-Nicotine, when administered into the mid-fourth ventricle, produced analgesia in low doses and hyperalgesia in high doses. Naltrexone and mecamylamine, when administered into the fourth ventricle, produced a dose-related analgesia. Doses of naltrexone and mecamylamine which antagonize maximally hyperalgesic doses of (-)-nicotine and ethylketazocine did not produce analgesia; however, larger doses produced analgesia. These observations suggest that analgesic doses do not involve prototypic kappa opioidergic or nicotinic mechanisms. These data confirm the existence of a medullary hyperalgesic center which may have both mu and kappa opioidergic as well as nicotinic mechanisms. Furthermore, these data indicate that this medullary hyperalgesic mechanism may have spontaneous or evoked tone and provide an explanation for the analgesic action of naltrexone and mecamylamine.
 ...
PMID:Pharmacologic characteristics of a medullary hyperalgesic center. 838 37

Rat/mouse hemokinin 1 (r/m HK-1) is a mammalian tachykinin peptide whose biological functions are not fully understood. Our recent report showed that i.c.v. administration of r/m HK-1 could produce dose- and time-related antinociceptive effect at nanomole concentration, and naloxone significantly antagonized this effect. Thus, we provide indirect evidence favoring a role of NK1 supraspinal receptors in the inhibitory control of descending pain pathways, a role that seems to partially involve the activation of the endogenous opioid systems. Based on this report, the present study was conducted to further investigate the direct functional interaction between supraspinal tachykinin (r/m HK-1) and opioid systems. The results demonstrate that i.c.v. administration of r/m HK-1 (5 nmol/kg) could significantly potentiate the antinociceptive effects of morphine which was injected at peripheral and supraspinal level. These antinociceptive effects were blocked by prior treatment with the classical opioid receptors antagonist naloxone, indicating that the potentiated analgesic response is mediated by opioid-responsive neurons. Consistent with previous biochemical data, a likely mechanism underlying the peptide-mediated enhancement of opioid analgesia may center on the ability of r/m HK-1 to release endogenous opioid peptides. We suggest that there may be a cascade amplification mechanism in pain modulation when the two agents were co-administrated. The synergistic analgesic relationship of morphine and r/m HK-1 established here supports the hypothesis that supraspinal tachykinin and peripheral and central opioid systems have a direct functional interaction in the modulation of local nociceptive responses.
 ...
PMID:Rat/mouse hemokinin-1, a mammalian tachykinin peptide, markedly potentiates the antinociceptive effects of morphine administered at the peripheral and supraspinal level. 1662 Oct 52

Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.
 ...
PMID:In vivo characterization of the effects of human hemokinin-1 and human hemokinin-1(4-11), mammalian tachykinin peptides, on the modulation of pain in mice. 1826 87

The current study evaluated the effects of hemopressin (HP) on pain modulation by endokinin A/B (EKA/B) and endokinin C/D (EKC/D) at the supraspinal level in mice. Intracerebroventricular administration of HP (10 nmol) fully antagonized the hyperalgesia induced by EKA/B (10, 30, and 100 pmol), and induced a dose-dependent potent analgesic effect. HP at different concentrations (10 pmol, 100 pmol, and 1 nmol) showed varying effects on the analgesic effect of EKA/B (3 nmol). HP extended the duration of the analgesic effect of EKC/D (3 nmol). Moreover, HP at different concentrations (10 pmol, 5 pmol, 1 pmol, and 100 fmol) co-administered with EKC/D (30 pmol) induced significant analgesia at two different time points: 5 min and 50 min. To investigate the antinociceptive mechanism, we used SR140333B and SR142801. HP (1 pmol) potentiated the analgesic effect of SR140333B (100 pmol)+EKA/B (30 pmol) in 5-10 min, while HP (100 pmol) had no effect in the analgesia induced by SR140333B (3 nmol)+EKA/B (3 nmol). HP (1 nmol) fully inhibited the analgesic effect of SR140333B (3 nmol)+EKC/D (3 nmol) or SR142801 (3 nmol)+EKC/D (3 nmol). HP (1 pmol) weakened the analgesic effect of SR142801 (100 pmol)+EKA/B (30 pmol), but HP (100pmol) strengthened the analgesic effect of SR142801 (3 nmol)+EKA/B (3 nmol). These findings may pave the way for a new strategy on investigating the interaction between tachykinins and opioids on pain modulation.
 ...
PMID:Effects of endokinin A/B and endokinin C/D on the antinociception properties of hemopressin in mice. 2295 22


1 2 Next >>